Production of dihydrovitamin k1



United States Patent 2,906,780 PRODUCTION OF DIHYDROVITAMIN K Ralph F.Hirschmaun, Westfield, Norman L. Wendler,

Summit, and Richard Miller, New Brunswick, N.J., assignors to Merck &Co., Inc., Railway, N.J., a corporation of New Jersey N Drawing.Application January '12, 1954 Serial No. 403,638

2 Claims. (Cl. 260-625) This invention relates to vitamin K Moreparticularly, this invention is concerned with novel monocarboxylic acidesters of 2-methyl-3-phytyl-l,4-naphthohydroquinone and processes ofproducing these compounds. Such compounds possess vitamin K activity andare useful intermediates in the synthetic production of vita- Ill I1 K1.

In the usual method for the commercial production of vitamin K2-methyl-1,4-naphthohydroquinone is reacted with phytol at about 80 C.for about 48 hours in the presence of oxalic acid to produce2-methyl-3-phytyl-l,4- naphthohydroquinone which is subsequentlyoxidized quantitatively to 2-methyl-3-phytyl-1,4-naphthoquinone (vitaminK The described condensation not only re quires an undesirably longreaction period which seriously limits production but also restricts theuse of equipment employed in the reaction from use in other operations.In'addition this reaction results in formation of appreciable quantitiesof the undesirable angular by-product 2-methyl-2-phytyl-1,4-naphthohydroquinone. Most serious however, is thelow yield obtained in this reaction which seldom exceeds about 25% ofthe desired product. Besides these disadvantages the resulting2-methyl-3-phytyl- 1,4-naphthohydroquinone must be isolated from variouscontaminating side products formed in the reaction mixture by tediousand time consuming methods.

An ultimate object of this invention is to provide a method of producingvitamin K in greatly increased yield. Another object is to provide novelchemical compounds which are useful intermediates in the syntheticproduction of vitamin K and processes of preparing such intermediates. Afurther object. of this invention is to substantially reduce theover-all time required to produce vitamin K synthetically. Other objectswill appear from the following description of the invention.

These and other objects have been realized according to the presentinvention by the discovery that phytol can be condensed with al-monocarboxylic acid ester of 2-" methyl-1,4-naphthohydroquinone toproduce the corresponding novel l-monocarboxylic acid ester of2-methyl-3- phytyl-l,4-naphthohydroquinone. This reaction may beillustrated as follows:

wherein R represents an acyl group.

2,906,780 Patented Sept. 29, 1959 over the prior art procedurepreviously described.

-Ainongst advantages that might be mentioned are a reduction in thereaction period from 48 hours to about 6 hours and, in some cases, to aslittle as 15 minutes. Besides reducing the reaction time the process ofthis invention consistently gives yields of the desired reaction productwhich are about 2 times larger than those previously attained. Thus,yields by prior art methods usually average about 25% whereas with thenovel process of this invention yields of 50% or more of thosetheoretically obtainable of the desired product are attained.Furthermore the resulting novel l-monocarboxylic acid esters of2-methyl-3-phytyl-1,4-naphthohydroquinone can be hydrolyzed to2-methyl-3-phytyl-l,4-naphthohydroquinoneand the latter compound canthen be oxidized to vitamin K by the usual procedures with substantiallyquantitative I results.

In general, any suitable l-monocarboxylic acid ester ofZ-methyl-1,4-naphthohydroquinone can be employed as a reactant in thisnew process. Thus, the acyloxy substituent present at the 1 position ofthe naphthohydroquinone nucleus may be an alkylacyloxy, arylacyloxy oraralkylacyloxy group derived from a monocarboxylic acid. Ordinarilyhowever, it is preferred to efiect the described novel condensationusing a l-monocarboxylic acid ester of 2-met-hyl-1,4-naphthohydroquinone in which the acyloxy group contains 8carbons or less. Specific examples of such compounds which can be usedin this invention that might be mentioned areZ-methyl-1,4-naphthohydroquinone-lacetate, 2 -methyl 1,4naphthohydroquinone 1 propionate,Z-methyl-l,4-naphthohydroquinone-l-butyrate, 2- methyl 1,4naphthohydroquinone 1 valerate, 2- methyl 1,4 naphthohydroquinone lcaproate, 2- methyl 1,4 naphthohydroquinone 1 caprylate, 2- methyl 1,4naphthohydroquinone 1 phenylacetate, 2 methyl 1,4 naphthohydroquinone 1benzoate and the like. These and similar esters can be prepared by theapplication of procedures in the literature, one source being US. PatentNo. 2,334,669.

Pursuant to the subject invention it has been found that thecondensation of a l-monocarboxylic acid ester of 2-methyl-l,4-naphthohydroquinone with phytol to produce the correspondingl-monocarboxylic acid ester of 2- methyl-3-phytyl-1,4-naphthohydroquinone can be brought about by the use of asuitable dehydrating catalyst. To obtain the advantages of this novelprocess-it is essential that a dehydrating catalyst be utilized in thereaction which is substantially insoluble i.e. heterogeneous, in thereaction medium, is strongly acidic and preferably has a pH of about 2to 4.5 in water and which does not form esters with phytol. Catalystswhich do not have these properties may effect the reaction but the timerequired is unduly long and the desired product is obtained in lowyield. Included among the catalysts which are considered suitable foreffectingthis reaction that might be mentioned are alkali metalbisulfates such as sodium bisulfate and potassium bisulfate and cationexchange resins on the hydrogen cycle such as those of the phosphonicThis reaction possesses several noteworthy advantages and phosphonousacid type, illustrations of which are Duolite, C-60 and Duolite C-61manufactured by Chemical Process Co., Redwood City, California.

Reaction between the l-monocarboxylic acid ester of 2-methyl-l,4-naphthohydroquinone and phytol is conveniently achieved bycontacting the reactants and catalyst in the presence of a suitablereaction medium at an elevated temperature, preferably from about 65 toC. Broadly, any inert organic solvent in which the reactants are solublemay be used as the reaction medium although, since the reaction isordinarily effected at elevated temperatures, it is desirable to employa solvent which boils above the reaction temperature. Furthermore toobtain,

the advantages of this novel process a solvent must be employed for thereaction in which the catalyst is substantially insoluble. Solvents suchas benzene, toluene, dioxane and ethylene glycol dimethyl ether areexamples of suitable reaction media in which the condensation may beeffected.

As previously indicated this condensation is readily effected attemperatures of 65-90 C. By carefully controlling the temperature withinthe range of 7085 C. optimum conditions interms of time and yield arerealized. Within the range of 70-85 C. a reaction time of 1 to 3 hoursis entirely adequate whereas with lower temperatures reaction times upto 6 hours are sometimes needed. At higher temperatures the reactiongoes to completion much quicker, often in about 15 minutes, but thereaction is somewhat more difiicult to control.

The quantity of reactants is not critical but it has been foundadvantageous to use an excess of the l-monocarboxylic acid ester ofZ-methyl-1,4-naphthohydroquinone and preferably at least two and up to10 moles of this reactant to each mole of phytol. Excess startingmaterial may be recovered unchanged by ordinary methods after thereaction has been completed. The catalyst may be employed in anyconcentration suitable for promoting the reaction but to insure maximumreaction large amounts should be utilized.

Following completion of the reaction the desired 1- monocarboxylic acidester of 2-methyl-3-phytyl-1,4- naphthohydroquinone is recovered andpurified. Thus, the reaction mixture may be cooled to about roomtemperature and filtered to remove the catalyst. The excessl-monocarboxylic acid ester of 2-methyl-l,4-naphthohydroquinone used inthe reaction is conveniently separated by evaporating the filtrate to asmall volume and extracting the residue with low boiling petroleum ether(B.P. 30-60 C.). The excess starting material is insoluble in petroleumether and is separated by filtration. The petroleum ether solution isextracted with dilute aqueous potassium hydroxide to remove impurities,and by evaporating the petroleum ether fraction the desiredl-rnonocarboxylic acid ester of 2-methyl-3-phytyl-1,4-naphthohydroquinone is isolated.

The described condensation may be specifically illustrated by thereaction of 2-methyl-1,4-naphthohydroquinone-l-acetate with phytol inthe presence of an alkali metal salt such as potassium bisulfate to form2- methyl-3-phytyl-1,4-naphthohydroquinone-l-acetate. Similarly2-methyl-1,4-naphthohydroquinone-l-propionate is reacted with phytol inthe presence of an alkali metal bisulfate or an equivalent catalyst toproduce Z-methyl- 3-phytyl-1,4-naphthohydroquinone-1-propionate. In alike manner starting with other appropriate reactants there is obtained2-methyl-3-phytyl-1,4-naphthohydroquinonel-valerate,2-rnethyl-3-phytyl-1,4-naphthohydroquinone-1- butyrate,2-methyl-3-phytyl-1,4-naphthohydroquinone-1- caproate,2-methyl-3-phytyl-1,4-naphthohydroquinone-1- caprylate,2-methyl-3-phytyl-l,4-naphthohydroquinone-lphenylacetate, 2 methyl3-phyty1-1,4-naphthohydroquinone-lbenzoate and other similarl-monocarboxylic acid esters of2-methyl-3-phytyl-1,4-naphthohydroquinone. Thme compounds possess theactivity of vitamin K itself.

These l-monocarboxylic acid esters of 2-methyl-3-phytyl-1,4-naphthohydroquinone may be converted to vitamin K In thefirst step of this conversion the lmonocarboxylic acid ester of2-methyl-3-phytyl-1,4-

naphthohydroquinone is dissolved in a suitable solvent' such as lowboiling petroleum ether and the resulting solution is extracted withClaisens alkali. In this manner purification and unexpected solvolysisof the acyl group is achieved simultaneously to give an alkalinesolution of essentially pure 2-methy1-3-phytyl-1,4-naphthohydroquinone.To separate the product the resulting alkaline solution is diluted with3% aqueous sodium hydrosulfite and extracted with ethylether. The ethylether treated with an oxidizing agent such as silver oxide to produce2-methyl-3-phytyl-1,4-naphthoquinone or vitamin K The vitamin isconveniently isolated, after removal of solids from the reactionmixture, by evaporating the solvent.

The following examples are added to illustrate specific applications ofthe invention but it should be recognized that the scope of theinvention is not to be restricted to the particular embodiments of theinvention as disclosed in these examples.

EXAMPLE 1 2-m ethyl-3 -phytyl-1 ,4-naphthohydroqui none-1 -acetate To 15ml. of dioxane is added 1.48 g. of phytol, 6.03 g. ofZ-methyl-1,4-naphthohydroquinone-l-acetate and 3.02 g. of groundpotassium acid sulfate. After stirring to'elfect solution of the organiccompounds, the mixture is heated at about C. for one hour and twentyminutes. The reaction mixture is then cooled to room temperature andfiltered to remove the catalyst. The filtrate is evaporated underreduced pressure to a thin slurry, low boiling petroleum ether is addedand the mixture is cooled in an ice bath. The mixture is filtered andthe petroleum ether filtrate is extracted with 2% aqueous potassiumhydroxide. The petroleum ether solution is evaporated to dryness underreduced pressure to obtain2-methyl-3-phytyl-1,4-naphthohydroquinone-l-acetate.

The product of this example is converted to vitamin K as follows:

The 2-methyl-3-phytyl-1,4-naphthohydroquinone-1-acetate'is added topetroleum ether and the resulting solution is extracted under nitrogenwith 50 ml. of Claisens alkali (prepared by dissolving 17.5 g. ofpotassium hydroxide in 12.5 ml. of water and diluting to 50 ml. withmethanol). The aqueous alkaline solution is diluted with a 3% aqueoussolution of sodium hydrosulfite, the mixture is extracted with ethylether and the ether extract is dried over magnesium sulfate. Afterconcentrating the solution to a small volume, 2.0 g. of silver oxide and2.0 g. of magnesium sulfate are added to the etheral solution followedby shaking for 30 minutes. After filtering, the desired vitamin K isrecovered by evaporating the filtrate to dryness under reduced pressure.

EXAMPLE 2 2-methyl-3-phytyl-1 ,4-naphthohydroquinone-I -pr0pi0nate To 16ml. of dioxane is added 1.48 g. of phytol, 11.60 g. of2-methyl-1,4-naphthohydroquinone-1-propionate and 3.02 g. of freshlyground potassium acid sulfate. The mixture is heated under nitrogen at76 C. for one hour and twenty minutes. After cooling to room temperaturethe reaction mixture is filtered to remove the catalyst. The filtrate isevaporated under reduced pressure until very little solvent remains. Tothe residue is added 27 ml. of petroleum ether (B.P. 3060 C.). Aftercooling for one hour in the refrigerator excess starting material isremoved by filtration and the filtrate is extracted with 2% aqueouspotassium hydroxide containing a small amount of sodium hydrosulfite.The petroleum ether layer is evaporated under reduced pressure to give2- methyl-3-phytyl 1,4-naphthohydroquinone-1-propionate.

The 2-methyl-3-phytyl-1,4-naphthohydroquinone-l-propionate is added to30 ml. of petroleum ether and shaken vigorously with 50 ml. of Claisensalkali containing 3.0 ml. of aqueous sodium hydrosulfite. The alkalineextract is separated and added to a mixture of 200 m1. of cold 3%aqueous sodium hydrosulfite and ml. of ether. The ether layer isseparated and dried over anhydrous magnesium sulfate. The other solutionof 2-methyl-3-phytyl 1,4 naphthohydroquinone is evaporated to about10-25 ml. and to it is added 2.08 g. of silver oxide in the presence ofmagnesium sulfate. The mixture is filtered' and by evaporating thefiltrate under reduced pressure to remove the solvent there is obtained2-methyl- 3-phytyl-1,4-naphthoquinone.

EXAMPLE 3 2-methyl-3-phytyl-1,4-naphthohydroquinone-1-butyrate 1.480 gm.of phytol, 11.60 g. of 2-methyl-1,4-naph thohydroquinone-l-butyrate and3.02 g. of sodium acid sulfate is added to 20 ml. of toluene and themixture is stirred well. The mixture is then heated at 80 C. for onehour, cooled and filtered. The toluene solution is evaporated to a smallvolume, triturated with petroleum ether, cooled and filtered. Thepetroleum ether filtrate is purified byextraction with 2% aqueouspotassium hydroxide. The desired 2-methyl-3-phytyl-l,4naphthohydroquinone-l-butyrate is recovered by evaporating the etherunder reduced pressure.

The procedure of this example is repeated starting with2-methyl-1,4-naphthohydroquinone-l-valerate and reacting it with phytolto form 2-methy1-3-phytyl-l,4-naphthohydroquinone-l-valerate. Similarly,other l-monocarboxylic acid esters of 2-methy1-1,4-naphthohydroquinonesuch as the caproate, caprylate and phenylacetate are reacted withphytol in the presence of an acidic salt such as an alkali metal acidsulfate to produce the corresponding2-methyl-3-phytyl-1,4-naphthohydroquinone-1-capro ate, l-caprylate andl-phenylacetate.

EXAMPLE 4 2-methyl-3-phytyl-1 ,4-naphthohydrquin0ne-1 -benz0ate To 25m1. of benzene is added 3 g. of 2-methyl-1,4-naphthohydroquinone-l-benzoate, 1 g. of phytol and 2 g. of potassiumacid sulfate. The mixture is refluxed for 2 hours, cooled and filtered.The benzene filtrate is reduced to a small volume of evaporation and lowboiling petroleum ether is added to the remaining solution. The mixtureis cooled, filtered and the filtrate is extracted with 2% aqueouspotassium hydroxide. The petroleum ether solution is evaporated todryness to obtain 2-methy1-3- phytyl-l,4-naphthohydroquinone-l-benzoate.

EXAMPLE 5 2-me1thyl-3-phytyl-1 a maphthohydroquinone-il -pr0pionate 11.6g. of 2-methy1-1,4-naphthohydroquinonel-propionate and 3.08 g. ofDuolite C-60, a cation exchange resin on the hydrogen cycle, are addedto 16 ml. of dioxane and the mixture heated to 75 C. Then 1.58 g. ofphytol in 4 ml. of dioxane is added over a 1 hour period. After theaddition of phytol has been completed heating is continued for 20minutes more. The reaction mixture is cooled to room temperature,filtered and the filtrate is reduced to a small volume by evaporationunder reduced pressure. Low boiling petroleum ether is added to theresidue, the mixture is cooled and filtered. The filtrate is extractedwith 2% aqueous potassium hydroxide containing a small amount of sodiumhydrosulfite. The petroleum ether layer is evaporated to isolate the 2-methyl-3-phyty1-1,4-naphthohydroquinone-l-propionate.

Various changes and modifications of the invention can be made and, tothe extent that such variations incorporate the spirit of thisinvention, they are intended to be included within the scope of theappended claims.

What is claimed is:

1. In a process for preparing dihydrovitamin K wherein al-monocarboxylic acid ester of 2-methyl-1,4-naphthohydroquinone (inwhich the acyl group is derived from a monocarboxylic acid having fromone to and including eight carbon atoms) is condensed with phytol toproduce the corresponding l-monocarboxylic acid ester ofZ-methy1-3-phytyl-1,4-naphthohydroquinone, the step which comprisescontacting the petroleum-ether-soluble products of the condensation stepwith Claisens alkali solution to effect hydrolysis of saidl-monocarboxylic acid ester of 2-methyl-3-phytyl-1,4-naphthohydroquinoneto dihydrovitamin K which thereupon passes into the alkaline layer ofthe system while the remaining petroleum-ether-soluble products of thecondensation step remain in the petroleum ether layer of the system,whereby, in this one step, there is efiected both the hydrolysis of saidl-monocarboxylic acid ester of 2-methyl-3-phytyl-1,4-naphthohydroquinoneto dihydrovitamin K and the purification of dihydrovitamin K 2. In aprocess for preparing dihydrovitamin K from a low boiling petroleumether solution of (i) a compound selected from Z-methyl 3phytyl-1,4-naphthohydroquinone-l-acetate and2-methyl-3-phytyl-1,4-naphthohydroquinone-l-propionate and (ii) thepetroleum-ether-soluble byproducts resulting when said compound wasformed, the principal such byproduct being phytadiene, the process whichconsists of contacting said petroleum ether solution with Claisensalkali solution, whereby the byproducts remain in the petroleum ethersolution which is the resulting upper phase of the system, while thecompound is hydrolyzed to dihydrovitamin K which thereupon dissolves inthe alkaline solution which is the resulting lower phase of the system,so that in one step the compound is hydrolyzed to dihydrovitamin K andthe principal impurity separated therefrom.

References Cited in the file of this patent UNITED STATES PATENTS2,325,681 Isler Aug. 3, 1943 2,456,686 Doisy et a1 Dec. 21, 19482,470,902 Rosenwald May 24, 1949 2,683,176 Isler et al. July 6, 1954 1).748.160 Reynolds et a1 May 29, 1956

1. IN A PROCESS FOR PREPARING DIHYDROVITAMIN K1 WHEREIN A 1-MONOCARBOXYLIC ACID ESTER OF 2-METHYL-1,4-NAPHTHOHYDROQUINONE (IN WHICH THE ACYL GROUP IS DERIVED FROM A MONOCARBOXYLIC ACID HAVING FROM ONE TO AND INCLUDING EIGHT CARBON ATOMS) IS CONDENSED WITH PHYTOL TO PRODUCE THE CORRESPONDING 1-MONOCARBOXYLIC ACID ESTER OF 2- METHYL-3PHYTYL-1,4-NAPHTHOHYDROQUINONE, THE STEP WHICH COMPRISES CONTACTING THE PETROLEUM-ETHER-SOLUTION PRODUCTS OF THE CONDENSATION STEP WITH CLAISEN''S ALKALI SOLUTION TO EFFECT HYDROLYSIS OF SAID 1-MONOCARBOXYLIC ACID ESTER OF 2-METHYL-3-PHYTYL-1,4-NAPHTHOHYDROQUINONE TO DIHYDROVITAMIN K1, WHICH THEREUPON PASSES INTO THE ALKALINE LAYER OF THE SYSTEM WHILE THE REMAINING PETROLEUM-ETHER-SOLUBLE PRODUCTS OF THE CONDENSATION STEP REMAIN IN THE PETROLEUM ETHER LAYER OF THE SYSTEM, WHEREBY, IN THIS ONE STEP, THERE IS EFFECTED BOTH THE HYDROLYSIS OF SAID 1-MONOCARBOXYLIC ACID ESTER OF 2-METHYL-3-PHYTYL-1,4-NAPHTHOHYDROQUINONE TO DIHYDROVITAMIN K1 AND THE PURIFICATION OF DIHYDROVITAMIN K1. 